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Oligopeptide linker intermediate and preparation method thereof

A technology of linker and intermediate, which is applied in the field of preparation method of oligopeptide linker and its intermediate, and can solve problems such as affecting product quality.

Active Publication Date: 2020-03-31
MABPLEX INT LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because in the Boc-Val-Cit-PAB molecule, there is an alcoholic hydroxyl group with a benzyl position, when HCl is used, the chlorination reaction of the alcoholic hydroxyl group will occur, and the corresponding benzyl chloride will be generated, which will affect the product quality.
When trifluoroacetic acid is used, the alcohol at the benzyl position will undergo esterification reaction to generate the corresponding trifluoroacetate, which requires an additional step of hydrolysis to obtain Val-Cit-PAB, an additional step, and alkaline hydrolysis has Risk of racemization of chiral centers on amino acid units

Method used

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  • Oligopeptide linker intermediate and preparation method thereof
  • Oligopeptide linker intermediate and preparation method thereof
  • Oligopeptide linker intermediate and preparation method thereof

Examples

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specific Embodiment

[0111] Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not indicate specific conditions are usually carried out according to conventional conditions or according to the conditions suggested by the manufacturer, and the reagents that do not indicate specific sources are conventional reagents purchased in the market. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

[0112] The unit of weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of solute in 100 ml of solution.

[0113] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in...

Embodiment 1

[0114] Embodiment 1 Teoc protecting group method prepares Val-Cit-PAB

[0115] (1) Preparation of Teoc-Val-Cit

[0116]

[0117] Add 14.16g of 2-(trimethylsilyl)ethanol (120mmol), 38.7g of N,N-diisopropylethylamine (300mmol), 30.4g of bis(p-nitrophenyl)carbonate (100mmol) to a 500mL single-necked bottle ), 400mL of acetonitrile, after the addition was complete, keep stirring at room temperature for 16h to form reaction solution 1. Add 14.08g of L-valine (120mmol) and 25.8g of N,N-diisopropylethylamine (200mmol) into a 1L single-necked bottle, and dissolve them with 400mL of water to form reaction solution 2. The reaction solution 1 was added into the reaction solution 2 under stirring state, and after stirring at room temperature for 16 h, the reaction solution was detected by LC-MS method to complete the reaction. After passing the test, the solvent of the reaction solution was rotary evaporated, and after evaporation to dryness, 500 mL of water was added, and 1 mol / L hy...

Embodiment 2

[0126] Embodiment 2 Cbz protecting group method prepares Val-Cit-PAB

[0127] (1) Preparation of Cbz-Val-Cit

[0128]

[0129] Add 10g of N-benzyloxycarbonyl-L-valine (ie Cbz-Val) (40mmol), 18.2g of N,N,N',N'-tetramethyl-O-(N-succinate Imide) urea tetrafluoroborate (60mmol), 15.5g N,N-diisopropylethylamine (120mmol), 300mL acetonitrile, after adding, stir at room temperature for 4h. After dissolving 7.7g of L-citrulline (44mmol) in 300ml of water, it was added to the above reaction system, stirred at room temperature for 16h, and the sample was detected by LC-MS, and the reaction was completed. While stirring, add 0.1 mol / L hydrochloric acid dropwise to adjust the pH value to 1, evaporate the solvent to dryness, add 800 mL of water, stir at room temperature for 16 h, and filter. After the filter cake was vacuum-dried, 400 mL of ethyl acetate was added, 400 mL of dichloromethane was stirred for 16 h, and then filtered. After the filter cake was vacuum-dried, 200 mL of eth...

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Abstract

The invention provides a novel oligopeptide linker intermediate and a preparation method thereof. The preparation method of the oligopeptide linker intermediate has the advantages of mild reaction conditions, easy realization, almost no side reaction in the reaction, few impurities, pure product and easy purification, and has unexpected technical effects.

Description

technical field [0001] The invention relates to the field of antibody-drug conjugates, in particular to a method for preparing an oligopeptide linker and an intermediate thereof. Background technique [0002] As a new type of biological missile, Antibody-Drug Conjugate (ADC) realizes the powerful combination of monoclonal antibody targeting and cytotoxicity of small molecule drugs, and has become the fastest-growing field of tumor targeted therapy one. The three components of ADC (antibody, cytotoxin and linker) together constitute a targeted drug delivery system, and the construction and optimization of the linker is the key to the development of this type of drug. Linkers are the basis for ADCs to effectively deliver cytotoxic drugs, and they are also the key factors that determine the toxicity of ADC products. Premature release of drugs in blood circulation can lead to systemic toxicity and low therapeutic index. By optimizing the existing conjugation technology, develo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/06C07K5/08C07K5/10C07K1/02A61K47/68A61K47/64A61P35/00
CPCC07K5/06C07K5/08C07K5/10A61K47/68A61K47/64A61P35/00C07K5/06052C07K5/06078C07K5/1008C07K5/0806A61K47/65C07K1/1077C07K1/063Y02P20/55C07K5/06191C07K5/0827C07K5/1027
Inventor 李乐乐黄长江
Owner MABPLEX INT LTD
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